According to the Christopher and Dana Reeve Foundation, there are over 1.2 million people living with spinal cord injury (SCI) in the United States alone [1]. Approximately 12,000 new cases in the US are reported each year [2]. The financial burden for a person living with cervical spinal cord injury ranges from 1 to 3 million dollars over his/her lifetime. Aside from the financial burden, people with SCI and their families and caregivers also deal daily with the physical, emotional, and social effects of this devastating condition. There are few treatments currently available or even being investigated in clinical trials that address neurological impairment following traumatic SCI. Therefore, there is a dire need for effective treatments that can reduce neurological deficit and improve a patient's quality of life following SCI.
SCI consists of two defined injury processes described in terms of primary and secondary injury. The primary injury to the spinal cord involves a mechanical injury such as contusion, compression, and/or laceration of the tissue. The secondary injury, immediately following the primary injury and lasting several weeks and months, involves a cascade of cellular and molecular events that results in increased blood brain barrier (BBB) permeability, ischemia and edema, apoptosis, glutamate excitotoxicity, inflammation, demyelination, ionic imbalance, axonal degeneration, reactive gliosis, and scar formation [3-6]. Neuroinflammation, as a part of the secondary injury process, is critical in the clearance of cellular debris and promoting regeneration at the injury epicenter. However, in the acute phase, immune reactive cells (neutrophils, microglia, and macrophages) can exacerbate the initial damage by producing pro-inflammatory cytokines, reactive oxygen species, matrix-metalloproteinase (MMP), and peroxynitrite resulting in further break down of the BBB, oxidative damage to DNA and lipids, protein nitrosylation, demyelination, apoptosis, and poor functional recovery [7].
The presence of immune reactive cells early at the injury epicenter has been shown to cause a substantial amount of by-stander damage to nearby healthy tissue. Neutrophils are observed as early as 6 hrs and peak at 24 hrs after injury [8-12] while monocytes and lymphocytes are observed at the injury site 3 days after SCI. Neutrophils can further increase the extent of the inflammatory response by producing pro-inflammatory mediators such as TNF-α, IL-1, and IL-8 [13]. MMP-9 and MMP-2 produced by neutrophils, macrophages, and endothelial cells can further break down the BBB and increase leukocyte infiltration [8]. The influx of neutrophils and hematogenous macrophages is a major source of reactive oxygen species and inducible nitrous oxide synthase (iNOS) [14, 15], and these agents can cause an increase in reactive oxygen radicals and nitrous oxide (NO) at the injury epicenter. Reactive oxygen radicals can react with NO to produce peroxynitrite (NO−) following injury [16]. The magnitude of the secondary damage can increase due to oxidation of proteins, DNA, and lipids by reactive oxygen radicals and peroxynitrite. In addition, activated macrophages can physically induce axonal retraction and impede axonal regeneration [17].
The recruitment of neutrophils and hematogenous macrophages to the injury epicenter occurs in a cascade-like fashion. Selectins and their counter-receptors initially mediate leukocyte rolling while integrins, I-type cellular adhesion molecule (I-CAM), V-CAM, and (PE)-CAM later mediate the tethering of leukocytes to the surface of endothelial cells [18-21]. Immune reactive cells are then activated by chemokines and chemoattractants via their respective G-protein coupled receptors. Activated immune reactive cells then extravasate into the injured tissue and produce more chemokines and pro-inflammatory cytokines to mediate the acute inflammatory response. Attenuating the inflammatory response following SCI by anti-inflammatory treatments such as high doses of methylprednisolone [22], depletion of macrophages [23], inhibition of MMP-9 [24], decreasing the availability of CAMs [25], and blocking neutrophils from entering the injury site [26, 27], has been shown to improve outcome following SCI in animals and humans.
Immunoglobulin G (IgG) isolated pooled human serum has been used clinically to treat autoimmune neuropathies such as Guillain-Barre syndrome. However, the mechanism underlying the observed benefits from IgG treatment is unclear. Many immune-modulating mechanisms for IgG have been proposed, and the exact mechanism could potentially be a combination of the following mechanisms. IgG preparations have been demonstrated to contain agonist anti-Fas antibodies, which induce monocyte and lymphocyte apoptosis via a caspase-dependent pathway [28]. IgG preparations also contain auto-antibodies toward the sialic acid-binding immunoglobulin—like lectin-9 (Siglec-9) that can induce neutrophil apoptosis via caspase-dependent pathways and pathways dependent on reactive oxygen species (ROS) [29]. In addition, IgG has been demonstrated to inhibit the production of MMP-9 in cultured macrophages via its Fc and F(ab)′2 fragments [30]. IgG has also been demonstrated to bind neutrophil chemotactic factors C3a and C5a at low affinity via the constant region of the F(ab)′2 fragment [31]. C5a is a potent chemotactic factor for neutrophil and macrophage recruitment and activation [32]. Recently, IgG immune-modulating mechanism is suggested to be via the regulation of Fcγ receptors expression, FcγRIIIA and FcγRIIB These receptors have low affinity to the Fc domain of the IgG molecules, and they are co-expressed on the surface of neutrophils, macrophages, mast cells, B-lymphocytes, and Natural Killer cells [33]. These Fcγ receptors work antagonistically against each other to maintain a constant balance between stimulatory and inhibitory signals in the immune system. The up-regulation of the activating FcγRIIIA receptor has been linked to immune-complex diseases and autoimmune disorders including, Arthus reaction, rheumatoid arthritis, glomerulonephritis, SLE, and ITP [33]. More specifically, sialylated N-linked glycan on the Fc fragment of IgG is required for the Fc fragment to bind to the SIGN-R1 (mice)/DC-SIGN (human) receptor on regulatory macrophages, which then up-regulate the expression of immune inhibitory FcγRIIB receptors on effector macrophages [34]. The sialic acid residue is part of a glycan, which is linked to the Fc fragment at the asparagines at position 297.
SCI is a devastating condition that can be accompanied by high levels of morbidity and mortality, while also severely reducing the quality of life of affected individuals. Current treatment options for clinicians and patients offer a low degree of efficacy and are often accompanied by undesirable complications, making the development of novel, clinically relevant therapeutic strategies a necessary goal. As mentioned above, the inflammatory response to SCI is highly complex and dynamic, contributing to both secondary injury mechanisms and wound repair pathways. It has proven difficult to target the deleterious aspects of the inflammatory response, while at the same time preserving or accentuating the beneficial elements.
Thus, there is a need for new therapeutic strategies for SCI patients.